RESUMEN

Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide because of its high morbidity and the absence of effective therapies. Even though paclitaxel is a powerful anticancer chemotherapy drug, recent studies have indicated its ineffectiveness against GC cells. Long non-coding RNA (lncRNA) PVT1 has a high expression in GC cells and increases the progression of tumors via inducing drug resistance. In the present study, the effects of the siRNA-mediated lncRNA PVT1 gene silencing along with paclitaxel treatment on the rate of apoptosis, growth, and migration of AGS GC cells were investigated. AGS cells were cultured and then transfected with siRNA PVT1 using electroporation. The MTT test was used to examine the effect of treatments on the viability of cultured cells. Furthermore, the flow cytometry method was used to evaluate the impact of treatments on the cell cycle process and apoptosis induction in GC cells. Finally, the mRNA expression of target genes was assessed using the qRT-PCR method. The results showed that lncRNA PVT1 gene suppression, along with paclitaxel treatment, reduces the viability of cancer cells and significantly increases the apoptosis rate of cancer cells and the number of cells arrested in the G2/M phase compared to the control group. Based on the results of qRT-PCR, combined treatment significantly decreased the expression of MMP3, MMP9, MDR1, MRP1, Bcl-2, k-Ras, and c-Myc genes and increased the expression of the Bax gene compared to the control group. The results of our study showed that lncRNA PVT1 gene targeting, together with paclitaxel treatment, induces apoptosis, inhibits growth, alleviates drug resistance, and reduces the migratory capability of GC cells. Therefore, there is a need for further investigations to evaluate the feasibility and effectiveness of this approach in vivo in animal models.

Asunto(s)

Apoptosis , Resistencia a Antineoplásicos , Silenciador del Gen , Paclitaxel , ARN Largo no Codificante , Neoplasias Gástricas , ARN Largo no Codificante/genética , Paclitaxel/farmacología , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Línea Celular Tumoral , Apoptosis/efectos de los fármacos , Apoptosis/genética , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Antineoplásicos Fitogénicos/farmacología , ARN Interferente Pequeño/genética

RESUMEN

OBJECTIVE: Precancerous lesions of gastric cancer (PLGC) are key pathological stages in the transformation of gastric "inflammation-cancer", and timely and effective intervention at this stage is of great importance in the prevention and treatment of gastric cancer. Zhiwei Fuwei Pills (ZWFW), as a traditional Chinese medicine formulation, has been proven to have good clinical efficacy in the treatment of PLGC, but its specific mechanism of action has not been fully explained. Thus, this study validated the efficacy and explored the potential mechanisms of ZWFW in treating PLGC by integrating network pharmacology analyses and experimental verification. METHODS: The TCMSP database was used to obtain the active ingredients of ZWFW and their corresponding targets, and the GeneCards database was used to retrieve PLGC-related targets. The intersecting targets between ZWFW and PLGC were obtained through mapping, and protein-protein interaction (PPI) networks and "drug-active ingredient-target" networks were constructed by using Cytoscape software. The DAVID database was used for GO functional enrichment analysis and KEGG pathway enrichment analysis. AutoDockTools software was used for molecular docking of key active ingredients and key targets. In order to verify the analysis results of network pharmacology, TEM and H&E were used to observe the effects of different dosage groups of ZWFW on gastric mucosal microvasculature in PLGC rats. Subsequently, the ELISA, IF, IHC, RT-PCR and western blot were used to detected the expression levels of relevant targets in the tissues, so as to verify the potential mechanism of ZWFW in intervening PLGC. RESULTS: After the screening, 258 effective active ingredients and 325 targets were obtained, and 1294 disease-related targets were determined, resulting in 139 intersection targets through mapping. The KEGG enrichment results showed that PI3K/Akt and HIF-1 signaling pathway might play important roles in the treatment mechanism of PLGC. The molecular docking results showed that active ingredients of ZWFW all had a strong affinity and stable structure with key targets, including AKT1 and VEGF. In vivo experiments confirmed that ZWFW could improve gastric mucosal microvascular abnormalities in PLGC, effectively intervene in gastric mucosal pathological grading. Meanwhile, compared with the model group, this formulation could reduce the expression levels of PI3K, Akt, mTOR, HIF-1α, and VEGF in gastric mucosa, showing a dose-effect relationship. CONCLUSION: ZWFW can intervene in the neovascularization and pathological evolution of PLGC, and this mechanism of action may be achieved by inhibiting abnormal activation of the PI3K/Akt/mTOR/HIF-1α/VEGF signaling pathway.

Asunto(s)

Medicamentos Herbarios Chinos , Neovascularización Patológica , Farmacología en Red , Lesiones Precancerosas , Neoplasias Gástricas , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Animales , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Neovascularización Patológica/tratamiento farmacológico , Masculino , Lesiones Precancerosas/tratamiento farmacológico , Lesiones Precancerosas/patología , Mapas de Interacción de Proteínas , Factor A de Crecimiento Endotelial Vascular/metabolismo , Ratas Sprague-Dawley , Ratas , Simulación del Acoplamiento Molecular , Angiogénesis

RESUMEN

BACKGROUND: This study aims to evaluate the short-term efficacy for locally advanced gastric cancer (LAGC) who accepted laparoscopic gastrectomy (LG) after neoadjuvant SOX versus SOX plus immune checkpoint inhibitors (ICIs). METHODS: LAGC patients who accepted LG after neoadjuvant SOX (SOX-LG, n = 169) and SOX plus ICIs (SOX + ICIs-LG, n = 140) in three medical centers between Jan 2020 and Mar 2024 were analyzed. We compared the tumor regression, treatment-related adverse events (TRAEs), perioperative safety between two groups, and explored the risk factors of postoperative complications (POCs) for LG after neoadjuvant therapy. RESULTS: The baseline characteristics were comparable between two groups (P > 0.05). SOX + ICIs-LG group acquired a higher proportion of objective response (63.6% vs. 46.7%, P = 0.003), major pathological response (43.6% vs. 31.4%, P = 0.001), and pathological complete response (17.9% vs. 9.5%, P = 0.030). There were no significant differences in the TRAEs rates, operation time, R0 resection, retrieved lymph nodes, postoperative first flatus, and hospitalized days, overall and severe POCs between two groups (P > 0.05). Patients in the SOX-ICIs-LG group had lower estimated blood loss (EBL) compared with SOX-LG (P = 0.001). Multivariate analysis showed that more EBL (P = 0.003) and prognostic nutritional index (PNI) < 40 (P = 0.005) were independent risk factors of POCs for LG after neoadjuvant therapy. CONCLUSION: Neoadjuvant SOX plus ICIs brings better tumor regression and similar TRAEs compared with SOX alone for LAGC. SOX + ICIs-LG is safe and feasible to conduct with less EBL. Surgeons should focus on the perioperative management to control POCs for patients with PNI < 40 and more EBL.

Asunto(s)

Gastrectomía , Inhibidores de Puntos de Control Inmunológico , Laparoscopía , Terapia Neoadyuvante , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/cirugía , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Masculino , Femenino , Gastrectomía/métodos , Gastrectomía/efectos adversos , Estudios Retrospectivos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Terapia Neoadyuvante/métodos , Persona de Mediana Edad , China/epidemiología , Laparoscopía/métodos , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Resultado del Tratamiento , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/epidemiología , Adulto

RESUMEN

BACKGROUND: Sitravatinib is a spectrum-selective tyrosine kinase inhibitor targeting TAM (TYRO3, AXL, MER), VEGFR-2, KIT, and MET. SAFFRON-104 (NCT03941873) was a multicohort phase Ib/II study investigating sitravatinib with/without tislelizumab, an anti-programmed cell death protein 1 (PD-1) antibody, in patients with advanced hepatocellular carcinoma (HCC) or gastric cancer/gastroesophageal junction cancer (GC/GEJC). METHODS: Eligible patients had histologically/cytologically confirmed advanced HCC or GC/GEJC. Phase I determined the recommended phase II dose (RP2D) of sitravatinib with/without tislelizumab. Phase II evaluated sitravatinib monotherapy in patients with pretreated HCC, and sitravatinib plus tislelizumab in anti-PD-(L)1-naïve or -treated HCC and anti-PD-(L)1-naïve GC/GEJC. Primary endpoints were safety/tolerability (phase I) and objective response rate (ORR) (phase II). RESULTS: At data cutoff (March 31, 2023), 111 patients were enrolled; 102 were efficacy-evaluable (median study follow-up 9.1 months [range: 0.7-36.9]). The RP2D of sitravatinib was determined as 120 mg orally once daily. In patients receiving sitravatinib monotherapy and sitravatinib in combination with tislelizumab, grade ≥ 3 treatment-related adverse events occurred in 14 (51.9%) and 42 (50.0%) patients, respectively. The ORR was 25% (95% confidence interval [CI]: 8.7-49.1) in patients with pretreated HCC receiving sitravatinib monotherapy. In patients receiving sitravatinib with tislelizumab, the ORR was 11.5% (95% CI 2.4-30.2) with anti-PD-(L)1-naïve HCC, 9.5% (95% CI 1.2-30.4) with anti-PD-(L)1-treated HCC, and 16.1% (95% CI 5.5-33.7) in patients with anti-PD-(L)1-naïve GC/GEJC. CONCLUSIONS: Sitravatinib with/without tislelizumab was generally well tolerated and showed preliminary antitumor activity in patients with advanced HCC and GC/GEJC.

Asunto(s)

Anticuerpos Monoclonales Humanizados , Carcinoma Hepatocelular , Unión Esofagogástrica , Neoplasias Hepáticas , Neoplasias Gástricas , Humanos , Masculino , Femenino , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacología , Anciano , Persona de Mediana Edad , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Unión Esofagogástrica/patología , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/patología , Anciano de 80 o más Años

RESUMEN

BACKGROUD: According to the 2020 statistics from the World Health Organization's International Agency for Research on Cancer (IARC), it is projected that there will be over 1 million new cases of gastric cancer (GC) patients worldwide in 2020, resulting in approximately 770 000 deaths. Gastric cancer ranks fifth in terms of incidence rate and forth in death rate among malignant tumors. Despite advancements in early diagnostic techniques, the incidence of GC has exhibited a marginal decline; nevertheless, the mortality rate remains elevated for advanced inoperable patients with no currently available efficacious treatment options. RECENT FINDING: Chinese medicine (CM) has emerged as an efficacious treatment for GC, gradually gaining acceptance and widespread usage in China. It exhibits distinctive advantages in the prevention and treatment of metastasis. CM and natural medicine possess the ability to elicit antitumor effects by augmenting immune cell population, enhancing immune cell activity, and improving the tumor immune microenvironment. CMs and natural remedies encompass a diverse range of types, characterized by multiple targets, pathways, and extensive pharmacological effects. Consequently, they have become a prominent research area among oncologists worldwide. Numerous studies have demonstrated that CM and natural medicine can directly or indirectly enhance innate immune system components (including macrophages, natural killer cells, and myeloid suppressor cells), adaptive immune system elements (such as T lymphocytes and regulatory T cells), relevant cytokines (e.g., IL-2, IL-4, IL-10, TNF-α), and PD-1/PD-L1 axis regulation, thereby bolstering the cytotoxicity of immune cells against tumor cells. CONCLUSIONS: This ultimately leads to an improved tumor immune microenvironment facilitating superior antitumor efficacy. This paper critically examines the role of CM and natural medicine in regulating immunotherapy for GC, aiming to establish a new theoretical framework for the clinical treatment and prevention of gastric cancer within the realm of CM.

Asunto(s)

Medicamentos Herbarios Chinos , Inmunoterapia , Medicina Tradicional China , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/terapia , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Medicamentos Herbarios Chinos/uso terapéutico , Inmunoterapia/métodos , Medicina Tradicional China/métodos , Microambiente Tumoral/inmunología , Microambiente Tumoral/efectos de los fármacos

RESUMEN

Anti-angiogenic agents elicit considerable immune modulatory effects within the tumor microenvironment, underscoring the rationale for synergistic clinical development of VEGF and immune checkpoint inhibitors in advanced gastric cancer (AGC). Early phase studies involving Asian patients demonstrated encouraging anti-tumor efficacies. We report the results of the REGOMUNE phase II study, in which Caucasian patients were administered regorafenib, a multi-tyrosine kinase inhibitor, in combination with avelumab, a PD-L1-targeting monoclonal antibody. This therapeutic regimen resulted in deep and durable responses in 19% of patients, with the median duration of response not yet reached. Notwithstanding, a significant proportion of AGC patients exhibited no therapeutic advantage, prompting investigations into mechanisms of inherent resistance. Comprehensive biomarker profiling elucidated that non-responders predominantly exhibited an augmented presence of M2 macrophages within the tumor microenvironment and a marked overexpression of S100A10 by neoplastic cells, a protein previously implicated in macrophage chemotaxis. Additionally, peripheral biomarker assessments identified elevated levels of cytokines, including CSF-1, IL-4, IL-8, and TWEAK, correlating with adverse clinical outcomes, thereby accentuating the role of macrophage infiltration in mediating resistance. These insights furnish an invaluable foundation for elucidating, and potentially circumventing, resistance mechanisms in current AGC therapeutic paradigms, emphasizing the integral role of tumor microenvironmental dynamics and immune modulation.

Asunto(s)

Antígeno B7-H1 , Resistencia a Antineoplásicos , Proteómica , Neoplasias Gástricas , Microambiente Tumoral , Humanos , Microambiente Tumoral/efectos de los fármacos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Neoplasias Gástricas/metabolismo , Proteómica/métodos , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Biomarcadores de Tumor , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Femenino , Masculino , Transcriptoma , Receptor de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Persona de Mediana Edad , Perfilación de la Expresión Génica

RESUMEN

DNA N6-methyladenine (6mA) demethylase ALKBH1 plays an important role in various cellular processes. Dysregulation of ALKBH1 is associated with the development of some cancer types, including gastric cancer, implicating a potential therapeutic target. However, there is still a lack of potent ALKBH1 inhibitors. Herein, we report the discovery of a highly potent ALKBH1 inhibitor, 1H-pyrazole-4-carboxylic acid derivative 29. The structure-activity relationship of this series of compounds was also discussed. Because of the poor cell membrane permeability of 29, we prepared a prodrug of 29 (29E), which showed excellent cellular activities. In gastric cancer cell lines HGC27 and AGS, 29E treatment significantly increased the abundance of 6mA, inhibited cell viability, and upregulated the AMP-activated protein kinase (AMPK) signaling pathway. In addition, the hydrolysis product 29 showed high exposure in mice after administration of 29E. Collectively, this research provides a new potent ALKBH1 inhibitor, which could serve as a lead compound for subsequent drug development.

Asunto(s)

Histona H2a Dioxigenasa, Homólogo 1 de AlkB , Antineoplásicos , Inhibidores Enzimáticos , Pirazoles , Neoplasias Gástricas , Humanos , Relación Estructura-Actividad , Histona H2a Dioxigenasa, Homólogo 1 de AlkB/metabolismo , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Animales , Pirazoles/farmacología , Pirazoles/química , Pirazoles/síntesis química , Ratones , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Línea Celular Tumoral , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacología , Ácidos Carboxílicos/síntesis química , Proliferación Celular/efectos de los fármacos , Estructura Molecular , Simulación del Acoplamiento Molecular , Ratones Desnudos , Ratones Endogámicos BALB C

RESUMEN

5-Fluorouracil (5-FU) is widely used in the treatment of gastric cancer, and the emergence of drug resistance and toxic effects has limited its application. Therefore, there is an urgent need for safe and effective novel drugs or new therapies. ß-Ionone (BI) is found in vegetables and fruits and possesses an inhibitory proliferation of tumor cells in vitro and in vivo. In this study, we investigated whether BI could enhance the inhibitory effects of 5-FU on the proliferation of gastric adenocarcinoma cells and the growth of gastric cancer cell xenografts in a mouse model. The effects of BI and 5-FU alone or their combination on the cell viability, apoptosis, and mitochondrial membrane potential, the cell cycle, and its related proteins-Cyclin D1, and CDK4 as well as PCNA and GSK-3ß were evaluated in SGC-7901 cells and MKN45 cells by MTT, MB, flow cytometry and Western blot. In addition, the effects of BI and 5-FU alone or their combination on the growth of SGC-7901 cell xenografts in nude mice were investigated. The results showed that BI significantly enhanced the sensitivity of gastric adenocarcinoma cells to 5-FU in vitro and in vivo, i.e. proliferation inhibited, apoptosis induced and GSK-3ß protein activated. Therefore, our results suggest that BI increases the antitumor effect of 5-FU on gastric adenocarcinoma cells, at least partly from an activated GSK-3ß signaling pathway.

Asunto(s)

Adenocarcinoma , Apoptosis , Proliferación Celular , Fluorouracilo , Glucógeno Sintasa Quinasa 3 beta , Ratones Desnudos , Norisoprenoides , Transducción de Señal , Neoplasias Gástricas , Animales , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Neoplasias Gástricas/metabolismo , Fluorouracilo/farmacología , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Proliferación Celular/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Línea Celular Tumoral , Norisoprenoides/farmacología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Adenocarcinoma/metabolismo , Ratones , Apoptosis/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Sinergismo Farmacológico , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones Endogámicos BALB C , Glucógeno Sintasa Quinasa 3/metabolismo , Supervivencia Celular/efectos de los fármacos , Quinasa 4 Dependiente de la Ciclina/metabolismo

RESUMEN

The clinical application of 5-fluorouracil (5-Fu), a potent chemotherapeutic agent, is often hindered by its well-documented cardiotoxic effects. Nevertheless, natural polyphenolic compounds like resveratrol (RES), known for their dual anti-tumor and cardioprotective properties, are potential adjunct therapeutic agents. In this investigation, we examined the combined utilization of RES and 5-Fu for the inhibition of gastric cancer using both in vitro and in vivo models, as well as their combined impact on cardiac cytotoxicity. Our study revealed that the co-administration of RES and 5-Fu effectively suppressed MFC cell viability, migration, and invasion, while also reducing tumor weight and volume. Mechanistically, the combined treatment prompted p53-mediated apoptosis and autophagy, leading to a considerable anti-tumor effect. Notably, RES mitigated the heightened oxidative stress induced by 5-Fu in cardiomyocytes, suppressed p53 and Bax expression, and elevated Bcl-2 levels. This favorable influence enhanced primary cardiomyocyte viability, decreased apoptosis and autophagy, and mitigated 5-Fu-induced cardiotoxicity. In summary, our findings suggested that RES holds promise as an adjunct therapy to enhance the efficacy of gastric cancer treatment in combination with 5-Fu, while simultaneously mitigating cardiotoxicity.

Asunto(s)

Apoptosis , Supervivencia Celular , Fluorouracilo , Resveratrol , Neoplasias Gástricas , Resveratrol/farmacología , Resveratrol/uso terapéutico , Fluorouracilo/farmacología , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Animales , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Línea Celular Tumoral , Cardiotónicos/farmacología , Cardiotónicos/uso terapéutico , Estilbenos/farmacología , Estilbenos/uso terapéutico , Humanos , Estrés Oxidativo/efectos de los fármacos , Antimetabolitos Antineoplásicos/farmacología , Autofagia/efectos de los fármacos , Masculino , Miocitos Cardíacos/efectos de los fármacos , Ratones , Movimiento Celular/efectos de los fármacos

RESUMEN

INTRODUCTION: The purpose of this research was to determine how the P53/microRNA-34a (miR-34a)/survivin pathway contributes to oxaliplatin-induced (L-OHP) cell inhibition in gastric cancer. METHODS: The BGC-823 gastric cancer cells were selected, and we examined their viability following treatment with L-OHP at different concentrations and time periods. The expression levels of miR-34a, P53, and survivin in the cells were determined. RESULTS: In the 12- and 24-h groups, drug concentration of 15 µg/cm² (p < .005 in both) significantly lowered cell viability. In comparison to the control group, miR-34a mRNA expression, P53 mRNA expression, and protein expression were all significantly greater in the 24-h group (p = .0324, p = .0069, p = .0260, respectively), but survivin mRNA and protein expressions were significantly lower than those in the control group (p = .0338, p = .0032, respectively). There was a significant decrease in gastric cancer cells in the miR-34a overexpression group (p = .0020), a significant increase in P53 mRNA and protein expression compared to the control group (p = .0080, p = .0121, respectively), and a significant decrease in survivin mRNA and protein expression compared to the control group. (p = .0213, p = .0069, respectively). CONCLUSION: Oxaliplatin inhibits tumor growth, invasion, and metastasis by upregulating miR-34a, activating the expression of the upstream P53 gene, and driving the downregulation of survivin (P53/miR-34a/survivin axis) in BGC-823 gastric cancer cells.

Asunto(s)

Regulación Neoplásica de la Expresión Génica , Proteínas Inhibidoras de la Apoptosis , MicroARNs , Oxaliplatino , Neoplasias Gástricas , Survivin , Proteína p53 Supresora de Tumor , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Neoplasias Gástricas/genética , MicroARNs/genética , Humanos , Oxaliplatino/farmacología , Survivin/metabolismo , Survivin/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Proteínas Inhibidoras de la Apoptosis/genética , Proteínas Inhibidoras de la Apoptosis/metabolismo , Antineoplásicos/farmacología , Compuestos Organoplatinos/farmacología , Compuestos Organoplatinos/uso terapéutico , Supervivencia Celular/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Progresión de la Enfermedad

RESUMEN

BACKGROUND: Nonresectable gastric cancer develops rapidly; thus, monitoring disease progression especially in patients receiving nivolumab as late-line therapy is important. Biomarkers may facilitate the evaluation of nivolumab treatment response. Herein, we assessed the utility of serum-based inflammatory indicators for evaluating tumor response to nivolumab. METHODS: This multicenter retrospective cohort study included 111 patients treated with nivolumab monotherapy for nonresectable advanced or recurrent gastric cancer from October 2017 to October 2021. We measured changes in the C-reactive protein (CRP)-to-albumin ratio (CAR), platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) in serum from baseline to after the fourth administration of nivolumab. Furthermore, we calculated the area under the receiver operating characteristic curves (AUC ROCs) for CAR, PLR, and NLR to identify the optimal cutoff values for treatment response. We also investigated the relationship between clinicopathologic factors and disease control (complete response, partial response, and stable disease) using the chi-squared test. RESULTS: The overall response rate (complete and partial response) was 11.7%, and the disease control rate was 44.1%. The median overall survival (OS) was 14.0 (95% CI 10.7‒19.2) months, and the median progression-free survival (PFS) was 4.1 (95% CI 3.0‒5.9) months. The AUC ROCs for CAR, PLR, and NLR before nivolumab monotherapy for patients with progressive disease (PD) were 0.574 (95% CI, 0.461‒0.687), 0.528 (95% CI, 0.418‒0.637), and 0.511 (95% CI, 0.401‒0.620), respectively. The values for changes in CAR, PLR, and NLR were 0.766 (95% CI, 0.666‒0.865), 0.707 (95% CI, 0.607‒0.807), and 0.660 (95% CI 0.556‒0.765), respectively. The cutoff values for the treatment response were 3.0, 1.3, and 1.4 for CAR, PLR, and NLR, respectively. The PFS and OS were significantly longer when the treatment response values for changes in CAR, PLR, and NLR were below these cutoff values (CAR: OS, p < 0.0001 and PFS, p < 0.0001; PLR: OS, p = 0.0289 and PFS, p = 0.0302; and NLR: OS, p = 0.0077 and PFS, p = 0.0044). CONCLUSIONS: Measurement of the changes in CAR, PLR, and NLR could provide a simple, prompt, noninvasive method to evaluate response to nivolumab monotherapy. TRIAL REGISTRATION: This study is registered with number K2023006.

Asunto(s)

Nivolumab , Neoplasias Gástricas , Humanos , Nivolumab/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/sangre , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Estudios Retrospectivos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Neutrófilos , Adulto , Anciano de 80 o más Años , Proteína C-Reactiva/análisis , Biomarcadores de Tumor/sangre , Plaquetas/patología , Antineoplásicos Inmunológicos/uso terapéutico , Linfocitos , Supervivencia sin Progresión , Recuento de Linfocitos , Resultado del Tratamiento , Curva ROC , Inflamación/sangre , Inflamación/tratamiento farmacológico

RESUMEN

BACKGROUND: Stage IV gastric cancer is a highly heterogeneous and lethal tumor with few therapeutic strategies. The combination of programmed cell death protein 1 inhibitors and chemotherapy is currently the standard frontline treatment regimen for advanced gastric cancer. Nevertheless, it remains a great challenge to screen the beneficiaries of immunochemotherapy and expand indications for this treatment regimen. METHODS: We conducted a pathological assessment to ascertain the importance of tertiary lymphoid structures based on the tissue samples collected from patients with stage IV gastric cancer (n=15) both prior to and following immunochemotherapy treatment. Additionally, we used spatial (n=10) and single-cell transcriptional analysis (n=97) to investigate the key regulators of tertiary lymphoid structures (TLSs). Multiplex immunofluorescence and image analysis (n=34) were performed to explore the association between tumor-infiltrating CXCL13+ CD160+ CD8+ T cells and TLSs. The relationship between CXCL13+ CD160+ CD8+ T cells and the responsiveness to immunotherapy was also evaluated by multiplex immunofluorescence and image analysis approaches (n=15). Furthermore, we explored the intrinsic characteristics of CXCL13+ CD160+ CD8+ T cells through various experimental techniques, including quantitative reverse transcription-PCR, western blot, and flow cytometry. RESULTS: We found that responders exhibited higher levels of TLSs and CXCL13+ CD160+ CD8+ T cells in biopsy tissues prior to immunochemotherapy compared with non-responders. Following conversion therapy, responders also had a higher percentage of mature TLSs and a higher number of CXCL13+ CD160+ CD8+ T cells in surgical resections. Moreover, we discovered that vitamin B6 in CD160+ CD8+ T cells could reduce the ubiquitination modification of HIF-1α by MDM2, thereby attenuating the degradation of HIF-1α. Consequently, this led to the transcriptional upregulation of CXCL13 expression, facilitating the recruitment of CXCR5+ B cells and the formation of TLSs. CONCLUSION: The number and maturity of TLSs, along with the extent of CXCL13+ CD160+ CD8+ T-cell infiltration, might function as potential indicators for assessing the effectiveness of immunotherapy in treating gastric malignancies. Furthermore, our research suggests that vitamin B6 could enhance the secretion of CXCL13 by CD160+ CD8+ T cells by reducing the degradation of HIF-1α. Additionally, we demonstrate that vitamin B6 supplementation or targeting pyridoxal kinase could substantially improve the efficacy of immunotherapies for gastric cancer.

Asunto(s)

Antígenos CD , Linfocitos T CD8-positivos , Quimiocina CXCL13 , Inmunoterapia , Neoplasias Gástricas , Estructuras Linfoides Terciarias , Humanos , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Neoplasias Gástricas/terapia , Neoplasias Gástricas/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Estructuras Linfoides Terciarias/inmunología , Quimiocina CXCL13/metabolismo , Inmunoterapia/métodos , Masculino , Femenino , Antígenos CD/metabolismo , Persona de Mediana Edad , Proteínas Ligadas a GPI/metabolismo , Anciano , Receptores Inmunológicos/metabolismo , Microambiente Tumoral , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Estadificación de Neoplasias

RESUMEN

Couroupita guianensis, a medicinal plant autochthonal to South America and South India, is widely used in the ethnomedicine of the indigenous peoples of these regions thanks to its alleged antimicrobial, anti-inflammatory, antioxidant and wound-healing properties. The majority of studies have mainly analyzed organic extracts of the Indian plant's flowers and leaves, with limited research on its bark decoction, traditionally used in Amazonian shamanic medicine. In this study, we investigated the anticancer effects of the bark decoction and its main fractions obtained through chromatographic separation, as well as the underlying molecular mechanisms in AGS gastric cancer cells. Viability, cell proliferation, cell cycle, apoptosis and protein expression related to these processes were evaluated. Both the bark decoction and fraction III significantly inhibited cell viability, and the cytotoxic effect was linked to cell cycle blockade and the induction of apoptosis also through an engulfment of the autophagic flux. Increased expression or activation of the key proteins (p53, p21, cdk2, Bak, caspases, pAMPK, pAkt, beclin, p62 and LC3BII) involved in these processes was observed. The results obtained confirmed an important anticancer effect of C. guianensis bark decoction, providing scientific validation for its use in traditional medicine and highlighting its potential as a therapeutic agent against gastric cancer.

Asunto(s)

Apoptosis , Proliferación Celular , Corteza de la Planta , Extractos Vegetales , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Extractos Vegetales/farmacología , Extractos Vegetales/química , Línea Celular Tumoral , Corteza de la Planta/química , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Antineoplásicos Fitogénicos/farmacología , Supervivencia Celular/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Autofagia/efectos de los fármacos

RESUMEN

Gastric cancer is one of the most common cancers worldwide, and new therapeutic strategies are urgently needed. Ferroptosis is an intracellular iron-dependent cell death induced by the accumulation of lipid peroxidation, a mechanism different from conventional apoptosis and necrosis. Therefore, induction of ferroptosis is expected to be a new therapeutic strategy. Glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1) have been identified as the major inhibitors of ferroptosis. Herein, we performed immunohistochemistry for GPX4, FSP1, and 4-HNE using tissues from patients with gastric cancer and investigated the relationship between these factors and prognosis. Patients with high GPX4 expression or high GPX4 expression and low 4-HNE accumulation tended to have a poor prognosis (p = 0.036, 0.023), whereas those with low FSP1 expression and high 4-HNE accumulation had a good prognosis (p = 0.033). The synergistic induction of cell death by inhibiting GPX4 and FSP1 in vitro was also observed, indicating that the cell death was non-apoptotic. Our results indicate that the expression and accumulation of lipid peroxidation-related factors play an important role in the clinicopathological significance of gastric cancer and that novel therapeutic strategies targeting GPX4 and FSP1 may be effective in treating patients with gastric cancer who have poor prognosis.

Asunto(s)

Biomarcadores de Tumor , Ferroptosis , Peroxidación de Lípido , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Neoplasias Gástricas , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Humanos , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Pronóstico , Femenino , Masculino , Biomarcadores de Tumor/metabolismo , Anciano , Persona de Mediana Edad , Ferroptosis/efectos de los fármacos , Línea Celular Tumoral , Aldehídos/metabolismo , Proteínas de Unión al Calcio/metabolismo , Proteínas de Unión al Calcio/genética

RESUMEN

The emergence of immunotherapy, particularly immune checkpoint inhibitors (ICIs), represents a groundbreaking approach to treating gastric cancer (GC). However, the prognosis of GC patients receiving ICI treatment is influenced by various factors. This manuscript identified sarcopenia and myosteatosis as inde-pendent prognostic factors impacting the outcomes of GC patients treated with ICIs. Additionally, this study introduced a visual predictive model to estimate the prognosis of GC patients. If confirmed by further studies, this observation could provide valuable insights to propel the advancement of personalized clinical medicine and the integration of precision medicine practices.

Asunto(s)

Inhibidores de Puntos de Control Inmunológico , Inmunoterapia , Neoplasias Gástricas , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/terapia , Neoplasias Gástricas/patología , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inmunoterapia/métodos , Inmunoterapia/efectos adversos , Resultado del Tratamiento , Pronóstico , Medicina de Precisión/métodos , Sarcopenia/inmunología , Sarcopenia/inducido químicamente

RESUMEN

Background: ß-glucan has been reported to be a potential natural immune modulator for tumor growth inhibition. We aimed to evaluate the efficacy and safety of ß-glucan plus immunotherapy and chemotherapy in the first-line treatment of advanced gastric adenocarcinoma. Methods: This is a phase IB, prospective, single-arm, investigator-initiated trail. Advanced gastric adenocarcinoma patients received ß-glucan, camrelizumab, oxaliplatin, oral S-1 every 3 weeks. The curative effect was evaluated every 2 cycles. The primary endpoints were objective response rate (ORR) and safety, with secondary endpoints were median progression-free survival (mPFS) and median overall survival (mOS). The exploratory endpoint explored biomarkers of response to treatment efficacy. Results: A total of 30 patients had been enrolled, including 20 (66.7%) males and all patients with an ECOG PS score of ≥1. The ORR was 60%, the mPFS was 10.4 months (95% confidence interval [CI], 9.52-11.27), the mOS was 14.0 months (95% CI, 11.09-16.91). A total of 19 patients (63.3%) had TRAEs, with 9 patients (30%) with grade ≥ 3. The most common TRAEs were nausea (53.3%). After 2 cycles of treatment, the levels of IL-2, IFN-γ and CD4+ T cells significantly increased (P < 0.05). Furthermore, biomarker analysis indicated that patient with better response and longer OS exhibited lower GZMA expression at baseline serum. Conclusions: This preliminary study demonstrates that ß-glucan plus camrelizumab and SOX chemotherapy offers favorable efficacy and a manageable safety profile in patients with advanced gastric adenocarcinoma, and further studies are needed to verify its efficacy and safety. Clinical Trial Registration: Chinese Clinical Trials Registry, identifier ChiCTR2100044088.

Asunto(s)

Adenocarcinoma , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Oxaliplatino , Neoplasias Gástricas , beta-Glucanos , Humanos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/mortalidad , Masculino , Persona de Mediana Edad , Femenino , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Adulto , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/mortalidad , beta-Glucanos/uso terapéutico , beta-Glucanos/administración & dosificación , Oxaliplatino/uso terapéutico , Oxaliplatino/administración & dosificación , Oxaliplatino/efectos adversos , Ácido Oxónico/administración & dosificación , Ácido Oxónico/uso terapéutico , Ácido Oxónico/efectos adversos , Tegafur/administración & dosificación , Tegafur/uso terapéutico , Tegafur/efectos adversos , Combinación de Medicamentos , Estudios Prospectivos , Resultado del Tratamiento

RESUMEN

BACKGROUND: Homologous recombination plays a vital role in the occurrence and drug resistance of gastric cancer. This study aimed to screen new gastric cancer diagnostic biomarkers in the homologous recombination pathway and then used radiomic features to construct a prediction model of biomarker expression to guide the selection of chemotherapy regimens. METHODS: Gastric cancer transcriptome data were downloaded from The Cancer Genome Atlas database. Machine learning methods were used to screen for diagnostic biomarkers of gastric cancer and validate them experimentally. Computed Tomography image data of gastric cancer patients and corresponding clinical data were downloaded from The Cancer Imaging Archive and our imaging centre, and then the Computed Tomography images were subjected to feature extraction, and biomarker expression prediction models were constructed to analyze the correlation between the biomarker radiomics scores and clinicopathological features. RESULTS: We screened RAD51D and XRCC2 in the homologous recombination pathway as biomarkers for gastric cancer diagnosis by machine learning, and the expression of RAD51D and XRCC2 was significantly positively correlated with pathological T stage, N stage, and TNM stage. Homologous recombination pathway blockade inhibits gastric cancer cell proliferation, promotes apoptosis, and reduces the sensitivity of gastric cancer cells to chemotherapeutic drugs. Our predictive RAD51D and XRCC2 expression models were constructed using radiomics features, and all the models had high accuracy. In the external validation cohort, the predictive models still had decent accuracy. Moreover, the radiomics scores of RAD51D and XRCC2 were also significantly positively correlated with the pathologic T, N, and TNM stages. CONCLUSIONS: The gastric cancer diagnostic biomarkers RAD51D and XRCC2 that we screened can, to a certain extent, reflect the expression status of genes through radiomic characteristics, which is of certain significance in guiding the selection of chemotherapy regimens for gastric cancer patients.

Asunto(s)

Biomarcadores de Tumor , Proteínas de Unión al ADN , Recombinación Homóloga , Aprendizaje Automático , Transducción de Señal , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/diagnóstico por imagen , Neoplasias Gástricas/patología , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/diagnóstico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Masculino , Femenino , Persona de Mediana Edad , Tomografía Computarizada por Rayos X/métodos , Estadificación de Neoplasias , Anciano , Regulación Neoplásica de la Expresión Génica , Radiómica

RESUMEN

In this study, we explored the potential of genetically engineered exosomes as vehicles for precise drug delivery in gastric cancer therapy. A novel antitumor strategy using biocompatible exosomes (Ex) was devised by genetically engineering adipose-derived stem cells to express an MKN45-binding peptide (DE532) on their surfaces. 17-(Dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG) was encapsulated in engineered exosomes, resulting in 17-DMAG-loaded DE532 exosomes. In both in vitro and in vivo experiments using mouse gastric cancer xenograft models, we demonstrated that 17-DMAG-loaded DE532 Ex exhibited superior targetability over DE532 Ex, 17-DMAG-loaded Ex, and Ex. Administration of the 17-DMAG-loaded DE532 Ex yielded remarkable antitumor effects, as evidenced by the smallest tumor size, lowest tumor growth rate, and lowest excised tumor weight. Further mechanistic examinations revealed that the 17-DMAG-loaded DE532 Ex induced the highest upregulation of the pro-apoptotic marker B-cell lymphoma-2-like protein 11 and the lowest downregulation of the anti-apoptotic marker B-cell lymphoma-extra large. Concurrently, the 17-DMAG-loaded DE532 Ex demonstrated the lowest suppression of antioxidant enzymes, such as superoxide dismutase 2 and catalase, within tumor tissues. These findings underscore the potential of 17-DMAG-loaded DE532 exosomes as a potent therapeutic strategy for gastric cancer, characterized by precise targetability and the potential to minimize adverse effects.

Asunto(s)

Antineoplásicos , Benzoquinonas , Exosomas , Lactamas Macrocíclicas , Neoplasias Gástricas , Exosomas/metabolismo , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Animales , Ratones , Benzoquinonas/farmacología , Benzoquinonas/administración & dosificación , Humanos , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Lactamas Macrocíclicas/farmacología , Lactamas Macrocíclicas/administración & dosificación , Lactamas Macrocíclicas/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto , Sistemas de Liberación de Medicamentos/métodos , Apoptosis/efectos de los fármacos , Ratones Desnudos

RESUMEN

A 36-year-old woman presented to our hospital with a complaint of melena. Examinations revealed type 3 gastric cancer with left supraclavicular lymph node(Virchow's node)and para-aortic lymph node(PAN)metastases. The patient was treated with S-1 and CDDP combination chemotherapy. After 2 courses of chemotherapy, the lymph node metastases were significantly reduced. Subsequently, a total gastrectomy with D2 plus PAN dissection was performed. Histopathological examination revealed the complete absence of cancer cells in both the primary lesion of the stomach and all dissected lymph nodes. No additional surgery or radiation therapy was performed for Virchow's node metastasis. Postoperatively, she received S-1 chemotherapy for 2.5 years. She remains well 9.5 years after the surgery, without any evidence of recurrent disease.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica , Combinación de Medicamentos , Gastrectomía , Metástasis Linfática , Ácido Oxónico , Neoplasias Gástricas , Tegafur , Humanos , Neoplasias Gástricas/patología , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/cirugía , Femenino , Adulto , Ácido Oxónico/administración & dosificación , Ácido Oxónico/uso terapéutico , Tegafur/administración & dosificación , Tegafur/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Factores de Tiempo , Cisplatino/administración & dosificación , Escisión del Ganglio Linfático

RESUMEN

Gastric cancer (GC) represents a major global health challenge as a highly prevalent disease with high mortality whose global incidence and mortality are predicted to worsen over the coming years. To date, our standard of care for advanced gastric cancer of combination chemotherapy and immunotherapy has a 1-year overall survival rate of 55%. Significant efforts have gone into identifying targetable alterations in gastric cancer, ultimately yielding the Fibroblast Growth Factor Receptors (FGFRs) family, specifically FGFR2 as a promising target. FGFR2 is overexpressed in GC, particularly diffuse-type GC, and is associated with poor prognostic outcomes. In recent years, there has been an increasing number of small molecule inhibitors and monoclonal antibodies targeting FGFR2 that have entered into clinical trials. Specifically for GC, these agents are currently being trialed in various phases as monotherapies or with standard-of-care treatments to make a clinically meaningful impact on what appears to be an important biological axis of GC. In this review, we outline the underlying biology of FGFR2, its putative role in GC, and the various FGFR2-targeted agents currently in clinical trials for gastric cancer patients as well as postulate some challenges in adopting these therapeutics for clinically meaningful benefit.

Asunto(s)

Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos , Neoplasias Gástricas , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/terapia , Humanos , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Terapia Molecular Dirigida/métodos , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología